Clinical Trials /

HER2-CAR T Cells in Treating Participants With Brain or Leptomeningeal Metastases

NCT03696030

Description:

This phase I trial studies the side effects and best dose of HER2-CAR T cells in treating participants with cancer that has spread to the brain or leptomeninges. HER2-CAR T cells delivered into the ventricles of the brain may recognize and kill tumor cells.

Related Conditions:
  • Cancer
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: HER2-CAR T Cells in Treating Participants With Brain or Leptomeningeal Metastases
  • Official Title: A Phase 1 Cellular Immunotherapy Study of Intraventricularly Administered Autologous HER2-Targeted Chimeric Antigen Receptor (HER2-CAR) T Cells in Patients With Brain and/or Leptomeningeal Metastases From HER2 Positive Cancers

Clinical Trial IDs

  • ORG STUDY ID: 17237
  • SECONDARY ID: NCI-2018-01270
  • SECONDARY ID: 17237
  • NCT ID: NCT03696030

Conditions

  • HER2/Neu Positive
  • Malignant Neoplasm
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Malignant Neoplasm in the Leptomeninges

Interventions

DrugSynonymsArms
Chimeric Antigen Receptor T-Cell TherapyCAR T-cell therapyTreatment (HER2-CAR T cells)

Purpose

This phase I trial studies the side effects and best dose of HER2-CAR T cells in treating participants with cancer that has spread to the brain or leptomeninges. HER2-CAR T cells delivered into the ventricles of the brain may recognize and kill tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the safety and recommended phase 2 dosing (RP2D) of intraventricularly
      administered memory-enriched autologous HER2(EQ)BBzeta/CD19t+ T cells (HER2-chimeric antigen
      receptor [CAR] T cells) in participants with brain and/or leptomeningeal metastases from HER2
      positive cancers.

      SECONDARY OBJECTIVES:

      I. Assess cerebrospinal fluid (CSF) and peripheral blood for HER2-CAR T cell persistence and
      endogenous immune system activation.

      II. Describe changes in cytokine levels in the CSF and peripheral blood. III. Describe
      changes in circulating tumor cells in the CSF. IV. In study participants who complete at
      least the first three cycles of HER2-CAR T cell infusions: describe the CNS clinical benefit
      defined as disease response rate based on Response Assessment in Neuro-Oncology Criteria
      (RANO) criteria (stable disease [SD], partial response [PR], or complete response [CR] in the
      brain).

      V. In study participants who complete at least the first three cycles of HER2-CAR T cell
      infusions: describe the systemic clinical benefit based on Response Evaluation Criteria in
      Solid Tumors (RECIST) criteria.

      VI. In study participants who complete at least the first three cycles of HER2-CAR T cell
      infusions: estimate the median central nervous system (CNS) progression-free and overall
      survival rates (mPFS and mOS), (newly diagnosed versus recurrent metastases).

      VII. In study participants who undergo tumor resection or biopsy during or after study
      treatment or upon autopsy, evaluate the tumor micro-environment for: HER2-CAR T cell
      persistence, immune cell subsets, cytokine levels, HER2 antigen expression levels.

      VIII. Use biomathematical modeling of tumor growth to evaluate benefit of treatment.

      OUTLINE: This is a dose-escalation study.

      Participants receive HER2-CAR T cells via intraventricular administration over 5 minutes once
      weekly for 3 doses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up at 4 weeks, 3, 6, 8, 10,
      and 12 months, and then for up to 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (HER2-CAR T cells)ExperimentalParticipants receive HER2-CAR T cells via intraventricular administration over 5 minutes once weekly for 3 doses in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  SCREENING: Participant has newly diagnosed (not previously treated with radiation) or
                 recurrent brain and/or leptomeningeal metastases after radiation
    
                   -  Note: Participants with leptomeningeal metastasis (diagnosed by positive CSF
                      cytology or characteristic findings on brain or spine magnetic resonance imaging
                      [MRI]) may have concomitant brain metastases, but having both is not required
    
              -  SCREENING: Participant must have a Karnofsky performance status (KPS) >= 70
    
              -  SCREENING: Participant must have a life expectancy of >= 8 weeks
    
              -  SCREENING: The effects of HER2-CAR T cells on a developing fetus are unknown. For this
                 reason, women of child-bearing potential must have negative serum pregnancy test and
                 agree to use a reliable form of birth control prior to study entry and for at least
                 two months following duration of study participation. Male research participants must
                 agree to use a reliable form of birth control and not donate sperm during the study
                 and for at least six months afterwards
    
              -  SCREENING: Participant has a histologically confirmed cancer which is HER2+, defined
                 as 3+ by immunohistochemistry (IHC) or gene amplification by fluorescence in situ
                 hybridization (FISH)
    
              -  SCREENING: Participant must have the ability to understand and the willingness to sign
                 a written informed consent
    
              -  ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: At least 2 weeks must have elapsed since
                 the participant received his/her last dose of prior chemotherapy or radiation
    
              -  ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: Research participant must not require more
                 than 6 mg/day of dexamethasone (or the equivalent dose of another corticosteroid) on
                 the day of leukapheresis
    
              -  ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: Participant must be willing to undergo
                 placement of a temporary catheter for central venous access if s/he does not have
                 adequate peripheral venous access for collection of T cells
    
              -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Creatinine < 1.6 mg/dL
    
              -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: White blood cell (WBC) >
                 2,000/uL (or absolute neutrophil count [ANC] > 1,000)
    
              -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Platelets >= 100,000/uL
    
              -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: International normalized
                 ratio (INR) must be < 1.3
    
              -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Bilirubin < 1.5 mg/dL
    
              -  ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Alanine aminotransferase
                 (ALT) and aspartate aminotransferase (AST) < 2.5 X upper limits of normal
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Research participants will enroll onto the study once they meet
                 eligibility to proceed with CAR T cell infusion prior to cycle 1. Once enrolled,
                 subjects will be considered on ?active? treatment until they complete the dose
                 limiting toxicity (DLT) evaluation period (~21 days)
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Participant must be taking =< 6 mg/ day of dexamethasone (or the
                 equivalent dose of another corticosteroid) during CAR T cell therapy
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Participant does not have evidence of active infection and does not
                 have a fever exceeding 38.5 degrees C; there is an absence of positive blood culture
                 for bacteria, fungus, or virus within 48-hours prior to HER2-CAR T cell infusion
                 and/or there aren?t any indications of meningitis
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: WBC > 2,000/uL (or ANC > 1,000)
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Platelets > 100,000/uL. However, if platelet level is between
                 75,000-99,000/uL then HER2-CAR T-cell administration may proceed after platelet
                 transfusion is given, and the post transfusion platelet count is >= 100,000/uL
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Serum creatinine < 1.8 mg/dL
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Serum total bilirubin or transaminases does not exceed 2 X upper
                 limits of normal
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Research participant does not require supplemental oxygen to keep
                 saturation greater than 95% and/or does not have presence of any radiographic
                 abnormalities on chest x-ray that are positive
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Research participant does NOT have any known history of congestive
                 heart failure (CHF) or cardiac symptoms consistent with New York Heart Association
                 (NYHA) classification III-IV within 6 months prior to day 1 of protocol treatment,
                 cardiomyopathy, myocarditis, Myocardial infarction (MI), exposure to cardiotoxic
                 medications or with clinical history suggestive of the above must have an
                 electrocardiogram (EKG) and echocardiogram (ECHO) performed within 42 days prior to
                 registration and as clinically indicated while on treatment
    
                   -  If the research participant has new symptoms of congestive heart failure (CHF),
                      cardiomyopathy, myocarditis, MI, or exposure to cardiotoxic medications, they
                      already had a cardiac consultation, creatinine phosphokinase (CPK), and troponin
                      testing at pre study deeming them fit for study participation
    
              -  ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF
                 HER2-CAR T CELLS: Participant has a released cryopreserved HER2-CAR T cell product
    
              -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participant must have at least 1 metastatic
                 brain lesion (measurable disease per RANO-Brain Metastases [BM] is not required?i.e.,
                 participant does not need to have at least 1 metastatic lesion >= 1 cm in longest
                 dimension) that is new or increasing in size, or CSF cytology and/or radiographic
                 findings consistent with leptomeningeal metastases
    
              -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participants whose brain metastases have been
                 treated with whole brain radiation (WBRT) or stereotactic radiosurgery (SRS):
                 previously radiated metastases must have >= 20% increase in longest diameter that is
                 also >= 5 mm absolute increase from prior brain MRI or histopathologically proven
                 recurrent tumor. Otherwise, new or not previously radiated lesions must be present
    
                   -  Note: Participants who have undergone local therapy (surgical resection or
                      biopsy, or SRS), must have recovered from all acute side effects before starting
                      treatment with HER2-CAR T cells
    
              -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: If a participant with brain metastases does
                 not meet the above criteria, but there is still concern by the study team that changes
                 in an enhancing brain lesion seen on brain MRI could be due to tumor progression, then
                 the participant can undergo resection or biopsy of the lesion(s) to distinguish
                 between tumor progression versus radiation necrosis. If there is histopathological
                 evidence of tumor progression, then the participant can proceed with study treatment
    
              -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Research participant does not have
                 uncontrolled seizure following surgery prior to starting the first CAR T cell dose
    
              -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participants must have recovered from
                 toxicity (=< grade 1) of prior therapy (excluding alopecia and peripheral neuropathy)
    
              -  ADDITIONAL ELIGIBILITY TO START CYCLE 1: Wash-out requirements (standard or
                 investigational). The required waiting period between the last dose of the most recent
                 chemotherapy agent(s) and first dose of HER2-CAR T cells is:
    
                   -  Four weeks for a cytotoxic chemotherapy, except for capecitabine, which will only
                      require a 1 week waiting period from the last dose (on a dosing schedule of bid x
                      14 days, then off x 7 days);
    
                   -  At least 6 weeks must have passed since the completion of a
                      nitrosourea-containing chemotherapy regimen;
    
                   -  At least four half-lives for a targeted agent
    
            Exclusion Criteria:
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant requires supplemental
                 oxygen to keep saturation greater than 95% and the situation is not expected to
                 resolve within 2 weeks
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participants with a known history of
                 congestive heart failure (CHF) or cardiac symptoms consistent with NYHA classification
                 III-IV within 6 months prior to day 1 of protocol treatment, cardiomyopathy,
                 myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications or with
                 clinical history suggestive of the above must have an EKG and echocardiogram (ECHO)
                 performed within 42 days prior to registration and as clinically indicated while on
                 treatment.
    
                   -  Research participants with new symptoms of CHF, cardiomyopathy, myocarditis, MI,
                      or exposure to cardiotoxic medications must have a cardiac consultation,
                      creatinine phosphokinase (CPK), and troponin testing at pre study and as
                      clinically indicated
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant requires dialysis
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant has uncontrolled seizure
                 activity and/or clinically evident progressive encephalopathy
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Failure of research participant to understand
                 the basic elements of the protocol and/or the risks/benefits of participating in this
                 phase 1 study. A legal guardian may substitute for the research participant
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is unwilling to stop treatment
                 with chemotherapy or endocrine therapy during the first 3 cycles of the HER2-CAR T
                 cell study
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has a coagulopathy or bleeding
                 disorder or cannot safely discontinue anticoagulation prior to placement of a Rickham
                 reservoir
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has a chronic or active viral
                 infection of the CNS
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has any uncontrolled illness,
                 including ongoing or active infection; participant has known active hepatitis B or C
                 infection; participants with any signs or symptoms of active infection, positive blood
                 cultures or radiological evidence of infections
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is human immunodeficiency virus
                 (HIV) seropositive based on testing performed within 4 weeks of screening
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has an autoimmune disease
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has another active malignancy
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participants with lung metastases (exception
                 may be allowed per principal investigator [PI] discretion for participants that are
                 not symptomatic from their lung metastases)
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is unable to undergo a brain MRI
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is breast feeding. Because there
                 is an unknown but potential risk for adverse events in nursing infants secondary to
                 treatment of the mother with HER2-CAR T cells, breastfeeding should be discontinued if
                 the mother wants to participate in this study
    
              -  EXCLUSION CRITERIA FOR STUDY SCREENING: Patient has a serious medical or psychiatric
                 illness that could, in the investigator?s opinion, potentially interfere with the
                 safety monitoring requirements and completion of treatment according to this protocol
          
    Maximum Eligible Age:75 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of dose limiting toxicities (DLTs)
    Time Frame:21 days post T cell infusion
    Safety Issue:
    Description:Rate and associated 90% Clopper and Pearson binomial confidence limits (90% CI) will be estimated for participants experiencing DLTs at the recommended phase 2 dose schedule.

    Secondary Outcome Measures

    Measure:HER2-CAR T cells in cerebrospinal fluid (CSF) and peripheral blood
    Time Frame:Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6,and 12 months, not progressed: baseline, 1, 3,6,8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Endogenous B cells in cerebrospinal fluid (CSF) and peripheral blood
    Time Frame:Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6,and 12 months, not progressed: baseline, 1, 3,6,8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:T cells in cerebrospinal fluid (CSF) and peripheral blood
    Time Frame:progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Myeloid cells in cerebrospinal fluid (CSF) and peripheral blood
    Time Frame:Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6,and 12 months, not progressed: baseline, 1, 3,6,8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Host immune subsets (e.g. T cell inhibitory/exhaustion markers, activation markers, and effector memory T cells) in cerebrospinal fluid (CSF) and peripheral blood.
    Time Frame:Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6,and 12 months, not progressed: baseline, 1, 3,6,8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Cytokine levels in CSF
    Time Frame:Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6,and 12 months, not progressed: baseline, 1, 3,6,8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Cytokine levels in peripheral blood
    Time Frame:Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6,and 12 months, not progressed: baseline, 1, 3,6,8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Circulating tumor cells in the CSF
    Time Frame:Measured over time from baseline through 1 year, the number of measurements is determined by whether or not the participant has progressed (progressed: baseline, 1, 3, 6,and 12 months, not progressed: baseline, 1, 3,6,8,10 and 12 months)
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Disease response in central nervous system (CNS) by Response Assessment in Neuro-Oncology (RANO) criteria
    Time Frame:progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
    Safety Issue:
    Description:Rates and 90% Clopper and Pearson Binomial Confidence limits will be calculated.
    Measure:Systemic disease response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
    Time Frame:progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
    Safety Issue:
    Description:Rates and 90% Clopper and Pearson Binomial Confidence limits will be calculated.
    Measure:Median CNS progression-free survival
    Time Frame:progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
    Safety Issue:
    Description:Kaplan Meier methods will be used.
    Measure:Median overall survival
    Time Frame:From time of surgery up to 15 years
    Safety Issue:
    Description:Kaplan Meier methods will be used.
    Measure:HER2-CAR T cells detected in the tumor micro-environment
    Time Frame:From time of surgery up to 15 years
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Immune cell subsets in the tumor micro-environment
    Time Frame:From time of surgery up to 15 years
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Cytokine levels in the tumor micro-environment
    Time Frame:From time of surgery up to 15 years
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:HER2 antigen expression levels
    Time Frame:From time of surgery up to 15 years
    Safety Issue:
    Description:Statistical and graphical methods will be used to describe the data.
    Measure:Biomathematical modeling of tumor growth: perfusion and growth parameters based on serial brain magnetic resonance imaging
    Time Frame:progressed: baseline, 1, 3, 6, and 12 months, not progressed: baseline, 1, 3, 6, 8,10 and 12 months)
    Safety Issue:
    Description:

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:City of Hope Medical Center

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